PCSK9 inhibitors in neurodegenerative disorders: mechanisms, therapeutic potential, and clinical implications
Open accessAbstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in hepatic cholesterol metabolism via low density lipoprotein receptor degradation. PCSK9 inhibitors have revolutionized lipid-lowering therapy, providing robust reduction of cardiovascular risk. Large-scale randomized controlled trials and long-term extensions (e.g., FOURIER and EBBINGHAUS trials) have shown no significant adverse effects of PCSK9 inhibitors on neuropsychological testing or patient-reported cognitive outcomes, even with prolonged and intensive lowering of low-density lipoproteins. Pre-clinical studies also suggest PCSK9 as a key regulator of neurobiological processes, including synaptic plasticity, amyloid-beta clearance, neuroinflammation, and blood–brain barrier integrity. Human genetic studies revealed complex, sometimes conflicting associations between PCSK9 variants and risk of Alzheimer’s disease, Parkinson’s disease, vascular dementia, and amyotrophic lateral sclerosis. In this review, we highlight the pathophysiologic mechanisms, emerging experimental therapeutics and clinical implications of PCSK9 inhibition in neurodegenerative disorders. Long-term adequately powered trials with robust neuropsychological, biomarker, and imaging endpoints, as well as mechanistic studies in human-derived models are needed to establish the cardiovascular and neurocognitive implications of PCSK9 inhibition and guide precision medicine strategies for those at elevated risk of neurodegeneration.
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Flagged first, then by citations
Cited by
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- Authors
- Wang, J. D. J., Teo, A. Y. T., Xiao, B., Chao, Y., Zhou, Z. D., Tan, B. J.-W., Chan, L.-L., Rosalie, E., & Tan, E.-K.
- Affiliations
- Nanyang Technological University (SG)
- National University Hospital (SG)
- National University of Singapore (SG)
- SingHealth (SG)
- Corresponding author
- Tan, Eng-King
- Venue
- Translational Neurodegeneration
- Published
- 2026-08-18
- Volume
- 15
- Issue
- 1
- ISSN
- 2047-9158 (ISSN-L)
- PMC
- PMC13483731
- OpenAlex
- W7203721681
- Cited by
- 0
- References
- 98
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Neurodegeneration (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Medical Research Council (LCG, STaR)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- PCSK9 inhibitors, PCSK9, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, vascular dementia, amyotrophic lateral sclerosis, LDL cholesterol lowering, cognitive safety, amyloid-beta clearance, neuroinflammation, blood-brain barrier, synaptic plasticity, cardiovascular risk, precision medicine
- MeSH terms
- Proprotein Convertase 9, PCSK9 Inhibitors, Animals, Humans, Neurodegenerative Diseases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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